Delivery of dry formulations of octreotide

ABSTRACT

Methods and devices are described for delivering octreotide to a patient, comprising implanting a controlled release composition for delivering octreotide, wherein the composition does not require hydration prior to implantation, and wherein the composition optionally comprises a release agent.

RELATED APPLICATIONS

This application is a Divisional Application of U.S. patent applicationSer. No. 12/171,999, filed Jul. 11, 2008, which is aContinuation-In-Part (CIP) of U.S. application Ser. No. 11/372,749,filed Mar. 10, 2006, which claims the benefit of U.S. ProvisionalApplication Ser. No. 60/660,930, filed Mar. 11, 2005. The entirecontents of these applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Acromegaly is a hormonal disorder that results when the pituitary glandproduces excess growth hormone (GH). It most commonly affectsmiddle-aged adults and can result in serious illness and prematuredeath. Once diagnosed, acromegaly is treatable in most patients, butbecause of its slow and often insidious onset, it frequently is notdiagnosed correctly. The most serious health consequences of acromegalyare diabetes mellitus, hypertension and increased risk of cardiovasculardisease. Patients with acromegaly are also at increased risk for polypsof the colon that can develop into cancer. When GH-producing tumorsoccur in childhood, the disease that results is called gigantism ratherthan acromegaly. Fusion of the growth plates of the long bones occursafter puberty so that development of excessive GH production in adultsdoes not result in increased height. Prolonged exposure to excess GHbefore fusion of the growth plates causes increased growth of the longbones and increased height.

Acromegaly is caused by prolonged overproduction of growth hormone (GH)by the pituitary gland. The pituitary is a small gland at the base ofthe brain that produces several important hormones to control bodyfunctions such as growth and development, reproduction, and metabolism.GH is part of a cascade of hormones that, as the name implies, regulatesthe physical growth of the body. This cascade begins in a part of thebrain called the hypothalamus, which makes hormones that regulate thepituitary. One of these, growth hormone-releasing hormone (GHRH),stimulates the pituitary gland to produce GH. Another hypothalamichormone, somatostatin, inhibits GH production and release. Secretion ofGH by the pituitary into the bloodstream causes the production ofanother hormone, called insulin-like growth factor 1 (IGF-1), in theliver. IGF-1 is the factor that causes the growth of bones and othertissues of the body. IGF-1, in turn, signals the pituitary to reduce GHproduction. GHRH, somatostatin, GH and IGF-1 levels in the body aretightly regulated by each other, and their levels are influenced byenvironmental stimuli such as sleep, exercise, stress, food intake andblood sugar levels. If the pituitary produces GH independent from thenormal regulatory mechanisms, the level of IGF-1 would rise, leading tobone growth and organ enlargement. Excess GH also causes changes insugar and lipid metabolism and can cause diabetes.

In over 90% of acromegaly patients, the overproduction of GH is causedby a benign tumor of the pituitary gland, called an adenoma. Thesetumors produce excess GH and, as they expand, compress surrounding braintissues, such as the optic nerves. This expansion causes the headachesand visual disturbances that are often symptoms of acromegaly. Inaddition, compression of the surrounding normal pituitary tissue canalter production of other hormones, leading to changes in menstruationand breast discharge in women and impotence in men.

In some patients, acromegaly is caused not by pituitary tumors but bytumors of the pancreas, lungs and adrenal glands. These tumors lead toan excess of GH, either because they produce GH themselves or, morefrequently, because they produce GHRH, the hormone that stimulates thepituitary to make GH. In these patients, the excess GHRH can be measuredin the blood and establishes that the cause of the acromegaly is not dueto a pituitary defect. When these non-pituitary tumors are surgicallyremoved, GH levels fall and the symptoms of acromegaly improve.

Acromegaly treatment regimens include reducing GH production to normallevels to relieve the pressure that the growing pituitary tumor exertson the surrounding brain areas, to preserve normal pituitary function,and to reverse or ameliorate the symptoms of acromegaly. Treatmentoptions include surgical removal of the tumor, drug therapy andradiation therapy of the pituitary.

Octreotide has been demonstrated to be effective in the management ofacromegaly. GH levels usually decrease within two hours following asubcutaneous octreotide injection. Octreotide results in a decrease inGH and IGF-1 levels in a majority of patients with normalization ofIGF-1 levels in up to 60% of patients, indicating biochemical remission.Most patients note a marked improvement in their symptoms of acromegalyincluding headaches, joint pains and diaphoresis very soon afterstarting octreotide therapy. Octreotide is currently available asSandostatin LAR® Depot, which is, upon reconstitution, a suspension ofmicrospheres containing octreotide acetate. Sandostatin LAR® Depot isthe only medication indicated for the long-term maintenance therapy inacromegalic patients. It is also indicated for the long-term treatmentof severe diarrhea and flushing episodes associated with metastaticcarcinoid tumors and profuse water diarrhea associated withVIP-secreting tumors. Sandostatin LAR® Depot is administered viaintramuscular injection every four weeks, following a titration period.Octreotide acetate has also been available in an immediate-releaseformulation, Sandostatin® Injection solution, which is required to beadministered by injection three times daily.

In patients who do not have a significant reduction in GH levels inresponse to intermittent octreotide injections, more frequent dosing ofoctreotide may result in a greater clinical response. Octreotide may beadministered continuously by a subcutaneous pump to patients withrefractory acromegaly to prevent escape of GH between injections.

In light of the efficacy of octreotide for treating acromegaly and lackof a controlled-release treatment method and formulation of octreotide,there is a clear need for a formulation and delivery method that candeliver octreotide over a period of time at a controlled rate to avoidthe complications of a patient's having to suffer, for example, multipleperiodic injections.

SUMMARY OF THE INVENTION

The present invention relates generally to an octreotide pharmaceuticalcomposition that can be used to treat individuals affected with hormonaldisorders. The present invention is preferably formulated as acontrolled-release formulation. In particular, the present invention isbased on the unexpected discovery that octreotide can be released at acontrolled rate using an implantable device, e.g., an implantable devicethat does not require priming prior to implantation.

In one embodiment, the present invention is directed to a method ofdelivering octreotide to a subject with a substantially zero-orderrelease profile over an extended period of time, but no less than aboutsix months, the method comprising subcutaneously implanting in thesubject at least one implantable device, wherein the at least oneimplantable device comprises a composition comprising octreotide,wherein the composition is encased in a hydrophilic polymer, and whereinthe implantable device is implanted in a dry state, such that thesubject receives on a daily basis over a period of at least about sixmonths dose amounts of octreotide, which are effective to treat thesubject. In a particular embodiment, the hydrophilic polymer comprisesone or more polyurethane-based polymers or methacrylate-based polymers.In one embodiment, the octreotide is in free form, salt form or in theform of a complex thereof, e.g., octreotide acetate. In a particularembodiment, the subject is afflicted with a GH or IGF-1 hormone disorderor its symptoms, e.g., acromegaly. In a particular embodiment, thesubject receives octreotide at an average rate ranging from about 75 μgper day to about 300 μg per day over a period of at least about sixmonths. In a particular embodiment, the dose amounts of octreotidereceived by the subject result in octreotide serum levels ranging fromabout 0.5 ng/ml to about 2 ng/ml. In a particular embodiment, thesubject receives an effective amount of octreotide for a period of atleast about twelve months. In a particular embodiment, the dose amountsof octreotide received by the subject result in octreotide serum levelsranging from about 0.8 ng/ml to about 1.8 ng/ml. In a particularembodiment, the dose amounts of octreotide received by the subjectresult in C_(max) for octreotide serum levels below about 1.3 ng/ml. Ina particular embodiment, the dose amounts of octreotide received by thesubject result in C_(max) for octreotide serum levels below about 1.0ng/ml. In a particular embodiment, release of octreotide occurs at leastthree to about ten days after implantation. In a particular embodiment,the subject is afflicted with a condition selected from the groupconsisting of: carcinoid syndrome, VIPomas, neuroendocrine tumors,proliferative diabetic retinopathy, rosacea, pancreatitis,gastrointestinal bleeding, pancreatic and intestinal fistulas,Graves-Basedow opthalmopathy, glaucoma, and symptoms associated withchemotherapy or AIDS.

The present invention provides a therapeutically-effective amount ofoctreotide over an extended period of time, preferably at least abouttwo months, more preferably about six months and up to about two years.The present invention also provides compositions that providecontrolled-release of octreotide over at least about two months,preferably about six months, and up to about two years.

Embodiments of the present invention relate to a pharmaceuticalcomposition comprising octreotide or salts, prodrugs or derivativesthereof, which can be used in the effective treatment of variousdiseases and conditions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the linear relationship between theequilibrium water content vs. the weight percent content ofhydroxypropyl methacrylate (HPMA) units in crosslinked HEMA/HPMApolymers at their maximum state of hydration.

FIG. 2 is a graph showing the release of octreotide from an implantformulation of the present invention.

FIG. 3 is a graph showing the release of octreotide from an implantformulation of the present invention.

FIG. 4 is a graph showing the release of octreotide from six differentimplant formulations of the present invention.

FIG. 5 is a graph showing the release of octreotide from differentimplant formulations of the present invention.

FIG. 6 is a graph showing octreotide and IGF-1 serum levels in a healthydog implanted with an octreotide formulation of the present invention.

FIG. 7 is a graph showing octreotide and IGF-1 serum levels in a groupof three healthy dogs implanted with one octreotide implant formulationof the present invention over a six month period.

FIG. 8 is a graph showing octreotide and IGF-1 serum levels in a groupof three healthy dogs implanted with two octreotide implant formulationsof the present invention over a six month period.

FIGS. 9A and 9B are graphs depicting the IGF-1 serum level and percentchange in eleven human subjects with acromegaly over six monthsimplanted with an octreotide formulation of the present invention,respectively.

FIG. 10 is a graph depicting octreotide serum levels in eleven humansubjects with acromegaly over six months implanted with an octreotideformulation of the present invention.

FIG. 11 is a graph depicting octreotide serum levels in two dogs oversix months implanted with an octreotide formulation of the presentinvention.

FIG. 12 is a graph depicting IGF-1 serum levels in two dogs over sixmonths implanted with an octreotide formulation of the presentinvention.

FIG. 13 is a graph showing serum octreotide levels after hydratedimplant delivery and dry implant delivery (see also Table 6).

FIG. 14 is a graph showing serum octreotide levels after hydratedimplant delivery and dry implant delivery (see also Table 6).

FIGS. 15A and 15B are graphs showing the levels of growth hormone afterdelivery of octreotide by hydrated and dry implants (GH concentration,upper panel; % GH decrease, bottom panel).

FIGS. 16A and 16B are graphs showing the levels of insulin-like growthfactor 1 (IGF-1) after delivery of octreotide by hydrated and dryimplants (IGF-1 concentration, upper panel; standard deviation, bottompanel).

FIGS. 17A and 17B are graphs showing the levels of growth hormone (GH)and insulin-like growth factor 1 (IGF-1) after delivery of octreotide byhydrated and dry implants (both panels show data from studies withvalues expressed as the percent of normal GH and IGF-1 levels,respectively).

DETAILED DESCRIPTION OF THE INVENTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularmolecules, compositions, methodologies or protocols described, as thesemay vary. It is also to be understood that the terminology used in thedescription is for the purpose of describing the particular versions orembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims. The termsused herein have meanings recognized and known to those of skill in theart, however, for convenience and completeness, particular terms andtheir meanings are set forth below.

The singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art. Although anymethods and materials similar or equivalent to those described hereincan be used in the practice or testing of embodiments of the presentinvention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated byreference to the extent they support the present invention. Nothingherein is to be construed as an admission that the invention is notentitled to antedate such disclosure by virtue of prior invention.

As used herein, the term “about: means plus or minus 10% of thenumerical value of the number with which it is being used. For example,about 50% means in the range of 45%-55%.

“Controlled-release formulation” refers to a formulation designed toconsistently release a predetermined, therapeutically-effective amountof drug or other active agent such as a polypeptide or a syntheticcompound over an extended period of time, with the result being areduction in the number of treatments necessary to achieve the desiredtherapeutic effect. A controlled-release formulation decreases thenumber of treatments necessary to achieve a desired effect in terms ofdecreased growth hormone levels or decreased IGF-1 levels, or animprovement in symptoms associated with, for example, acromegalyincluding but not limited to abnormal growth, carcinoid syndrome,VIPomas (Vasoactive Intestinal Peptide Secreting Adenomas),neuroendocrine tumors (specifically treating the symptoms of flushingand diarrhea), proliferative diabetic retinopathy, rosacea,pancreatitis, gastrointestinal bleeding, pancreatic and intestinalfistulas, Graves-Basedow opthalmopathy, glaucoma, or treating symptomsof chemotherapy and AIDS. The controlled-release formulations of thepresent invention achieve a desired pharmacokinetic profile in asubject, preferably commencement of the release of the active agentsubstantially immediately after placement in a delivery environment,followed by consistent, sustained, preferably zero-order or nearzero-order release of the active agent.

As used herein, the term “controlled-release” includes thepredetermined, consistent release of active agent from the dosageformulation at a rate such that a therapeutically beneficial blood levelbelow toxic levels of the active agent is maintained over a period, forexample, of at least about two months, about six months or more (e.g.,up to about two years).

The terms “patient” and “subject” mean all animals including humans.Examples of patients or subjects include humans, cows, dogs, cats,goats, sheep, and pigs.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention that are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response and the like. Their use iscommensurate with a reasonable benefit/risk ratio, and is effective fortheir intended use. Zwitterionic forms, where possible, are also usefulcompounds of the invention. The compounds of the present inventionadditionally can exist, for example, in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as, for example,water, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thepresent invention.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compounds of the above formula, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference in theirentireties.

The term “salts” refers to the relatively non-toxic, inorganic andorganic acid addition salts of compounds of the present invention. Thesesalts can be prepared in situ during the final isolation andpurification of the compounds or by separately reacting the purifiedcompound in its free base form with a suitable organic or inorganic acidand isolating the salt thus formed. Representative salts include theacetate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamineand the like (See, for example, S. M. Barge et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein byreference in its entirety).

“Treatment” refers to the administration of medicine or the performanceof medical procedures with respect to a patient, either for prophylaxis(prevention) or to cure the infirmity or malady in the instance wherethe patient is afflicted.

A “therapeutically effective amount” is an amount sufficient todecrease, prevent or ameliorate the symptoms associated with a medicalcondition. In the context of hormonal therapy it can also mean an amountsufficient to normalize body functions or hormone levels in disease ordisorders. For example, a therapeutically effective amount of acontrolled-release formulation of octreotide is a predetermined amountcalculated to achieve the desired effect, e.g., to effectively decreasegrowth hormone or IGF-1 levels in a patient.

The present invention can be utilized to treat a variety of hormonaldisorders, including, for example, acromegaly and gigantism, or otherdiseases, disorders or symptoms that are effectively treated with, forexample, octreotide, e.g., carcinoid syndrome, VIPomas (VasoactiveIntestinal Peptide Secreting Adenomas), neuroendocrine tumors(specifically treating the symptoms of flushing and diarrhea),proliferative diabetic retinopathy, rosacea, pancreatitis,gastrointestinal bleeding, pancreatic and intestinal fistulas,Graves-Basedow opthalmopathy, glaucoma, or treating symptoms ofchemotherapy and AIDS.

Acromegaly is characterized by a number of clinical features includingenlargement of the hands and feet, facial changes including frontalbossing, enlarged mandible and increased dental spacing, arthralgias,diaphoresis, sleep apnea, hypertension, diabetes mellitus andhypertrophic cardiomyopathy. Tumors that cause acromegaly frequentlycause local anatomic compression, resulting in, for example, visualfield deficits, headaches, hypopituitarism, and cranial nerve palsies.There is a 2 to 5 fold increase in the mortality rate in acromegalicpatients largely due to cardiovascular and cerebrovascular disease.There is also an increased rate of malignancy associated withacromegaly, with colon cancer the best characterized.

Carcinoid tumors usually appear in the appendix, bronchial tubes, colon,or small intestine and secrete chemicals that cause the dilation ofblood vessels-such as serotonin. Vasodilation may be responsible for thesymptoms usually observed with Carcinoid tumors—such as, for example,diarrhea, flushing and asthma. Depending on the hormones andbiochemicals secreted by carcinoid tumors a number of symptoms can bepresent. These are collectively known as “Carcinoid Syndrome”.Biochemically, people with Carcinoid tumors tend to produce moreserotonin, using the amino acid tryptophan as a base-serotonin isfurther broken down in the body to product 5-hydroxy indole acetic acid(5-HIAA) which is seen in the urine of the majority of such patients.Diagnostic tests on blood and urine would show a patient with aCarcinoid tumor-exhibits elevated urinary 5-HIAA, low blood tryptophan,high blood chromogranin A, and serotonin. Blood tests are also used tolevels of histamine, bradykinin, neurone-specific enolase, calcitonin,Substance-P, neurokinin-A, and pancreatic polypeptide.

An “OctreoScan” is a scanning test used to identify carcinoid tumors andneuroendocrine tumors. This scan utilizes a radioactive octreotidederivative called pentetreotide. Post-injection, this concentrates intissues expressing the somatostatin receptor. Neuroendocrine tumorsover-express the receptor and are imaged using this test.

As used herein, the term “octreotide” refers generally to all compoundscomprising the structure as shown, including various salt forms.Octreotide comprises an octapeptide with the following amino acidsequence: L-cysteinamide,D-phenylalanyl-L-cysteiny-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic(2→7)-disulfide;[R—(R*,R*)]. The structure of octreotide is shown below.

The chemical formula is C₄₉H₆₆N₁₀O₁₀S₂ and its molecular weight is1019.3 Da. Its therapeutic category is gastric anti-secretory agent. Theoctreotide of the present invention can exist in, for example, a freeform, a salt form or in the form of complexes thereof. Acid additionsalts can be formed with, for example, organic acids, polymeric acidsand inorganic acids. Acid addition salts include, for example, thehydrochloride and acetates. Complexes are formed, for example, fromoctreotide on addition of inorganic substances, e.g., inorganic salts orhydroxides such as Ca- and Zn-salts and/or addition of polymeric organicsubstances. The acetate salt is the preferred salt for formulations ofthe present invention.

Embodiments of the present invention provide a drug delivery device thatcan achieve the following objectives: a controlled-release rate (zero orabout zero order release rate) to maximize therapeutic effects andminimize unwanted side effects; a convenient way to retrieve the deviceif it is necessary to end the treatment; and an increase inbioavailability with less variation in absorption and no first passmetabolism.

The controlled-release pharmaceutical composition comprising octreotideacetate can be part of a controlled-release hydrogel device. Thecomposition of the present invention is capable of providing, uponadministration to a patient, a release profile of octreotide extendingover at least about two months, preferably at least about six months ormore, e.g., up to about two years. Octreotide can be contained withinthe hydrogel, for example, and the formulation releases atherapeutically effective amount of octreotide over an extended periodof time. The hydrogel can comprise a polymer selected frommethacrylate-based polymers, polyurethane-based polymers andcombinations thereof. A therapeutically effective amount is an amount ofoctreotide, preferably octreotide acetate, that when administered to apatient or subject, ameliorates a symptom of acromegaly. The formulationcan further include pharmaceutically acceptable excipients.

When the compositions of the present invention are administered to apatient, the concentration of octreotide in the patient's plasma overtime (release profile) can extend over a period of at least about twomonths, preferably about six months, and up to about two years. Thecompositions can provide a mean plasma concentration at steady state ofoctreotide in a human patient of from about 0.1 to about 9 ng/ml, about5 ng/ml to about 1 ng/ml, about 1 to about 2 ng/ml, or about 1.2 toabout 1.6 ng/ml. Steady state is the point at which the amount of drugadministered over a dosing interval equals the amount of drug beingeliminated over that same period.

The hydrophilic implant comprising the octreotide formulation can beformed from a xerogel such that it readily absorbs water. In a hydratedstate, the xerogel is referred to as a hydrogel. In either form,hydrated or unhydrated, it is biocompatible and non-toxic to the hostand non-biodegradable. It is water-swellable and water-insoluble. Whenthe hydrogel attains its maximum level of hydration, the water contentof the hydrogel is referred to as “equilibrium water content” (EWC). Thepercent water content of the hydrogel (any state of hydration) isdetermined as follows:

$\frac{{{weight}\mspace{14mu} {of}\mspace{14mu} {hydrogel}} - {{weight}\mspace{14mu} {of}\mspace{14mu} {dry}\mspace{14mu} {polymer}\mspace{14mu} ({xerogel})}}{{weight}\mspace{14mu} {of}\mspace{14mu} {hydrogel}} \times 100$

The hydrogel can be a homogeneous homopolymer or copolymer having apredetermined equilibrium water content (EWC) value formed by thepolymerization of a mixture of ethylenically unsaturated monomer A andethylenically unsaturated monomer B, for example, 2-hydroxyethylmethacrylate (HEMA) and hydroxypropyl methacrylate (HPMA). Thepredetermined EWC can be calculated by determining the EWC values of thehydrogel homopolymer of hydrophilic monomer A (homopolymer A) and thehydrogel homopolymer of hydrophilic monomer B (homopolymer B);determining the relationship of the EWC values of the homogeneouscopolymers AB versus the chemical composition of said copolymers AB;selecting the targeted EWC value and determining the chemicalcomposition of copolymer AB having the targeted EWC value; forming apolymerizable mixture of monomer A and monomer B in amounts sufficientto yield copolymer AB having the targeted EWC value; and effect thepolymerization reaction to yield copolymer AB characterized by thetargeted EWC value.

As used herein, “copolymer AB” or “copolymer AB consisting essentiallyof monomer A units and monomer B units” means that the additioncopolymerization of monomer A and monomer B has been effected throughthe polymerizable ethylenic bond of the monomers. By way ofillustration, if monomer A is 2-hydroxyethyl methacrylate and monomer Bis N-methylacrylamide, copolymer AB contains recurring monomer A unitsand recurring monomer B units.

Unless the context indicates otherwise, the term “copolymer” includespolymers made by polymerizing a mixture of at least two ethylenicallyunsaturated monomers.

As used herein, “HEMA unit(s)” refer to a structure recurring in thepolymer obtained by polymerizing hydrophilic material containing2-hydroxyethyl methacrylate (“HEMA”). By the term “HEMA unit(s)” ismeant the structure:

As used herein, “HPMA unit(s)” refers to a structure obtained bypolymerizing hydrophilic material containing hydroxypropyl methacrylate(“HPMA”). By the term “HPMA unit(s)” is meant the structure:

Liquid polymerizable material useful in the hydrophilic products includea wide variety of polymerizable hydrophilic, ethylenically unsaturatedcompounds, in particular, hydrophilic monomers such as, for example, themonoester of an acrylic acid or methacrylic acid with a polyhydroxycompound having an esterifiable hydroxyl group and at least oneadditional hydroxyl group such as, for example, the monoalkylene andpolyalkylene polyols of methacrylic acid and acrylic acid, e.g.,2-hydroxyethyl methacrylate and acrylate, diethylene glycol methacrylateand acrylate, propylene glycol methacrylate and acrylate, dipropyleneglycol methacrylate and acrylate, glycidyl methacrylate and acrylate,glyceryl methacrylate and acrylate, and the like; the 2-alkenamides,e.g., acrylamide, methacrylamide, and the like; the N-alkyl andN,N-dialkyl substituted acrylamides and methacrylamides such asN-methylmethacrylamide, N,N-dimethylmethacrylamide, and the like;N-vinylpyrrolidone; the alkyl-substituted N-vinylpyrrolidones, e.g.,methyl substituted N-vinylpyrrolidone; N-vinylcaprolactam; thealkyl-substituted N-vinylcaprolactam, e.g., N-vinyl-2-methylcaprolactam,N-vinyl-3,5-dimethylcaprolactam, and the like. Acrylic and methacrylicacid can also be useful in these formulations.

Mixtures of hydrophilic monomers are employed in the polymerizationreaction. The type and proportion of monomers are selected to yield ahomogeneous polymer, preferably a crosslinked homogeneous polymer, whichon hydration possesses the desired EWC value for the contemplatedapplication or use. This value can be predetermined by preparing aseries of copolymers using different monomer ratios, e.g., mixtures ofHEMA and HPMA of varying ratios, ascertaining the EWC values of thecopolymers, and plotting the relationship of % HPMA (or % HEMA) units inthe HPMA/HEMA copolymers versus weight percent EWC of the copolymers(FIG. 1).

In some instances the polymerization of certain hydrophilic monomericmixtures results in homogeneous hydrophilic copolymers that dissolve, toa varying extent, in an aqueous medium. In such cases, a small amount,e.g., up to 3 percent, of a copolymerizable polyethylenicallyunsaturated crosslinking agent, can be included in the monomeric mixtureto obtain homogeneous crosslinked copolymers that are water-insoluble aswell as water-swellable. Slightly crosslinked homopolymers of HEMA canhave an EWC value of, for example, about 38%. Crosslinked copolymers ofHEMA and HPMA have EWC values below about 38%. On the other hand,crosslinked copolymers of HEMA and acrylamide exhibit EWC values above38% (w/v), e.g., upwards to approximately 75%, and higher. Therefore,depending on the useful or effective elution rate of the activecompound, e.g., drug, that is required of a hydrogel delivery system fora particular application, one skilled in the art, by following theteachings disclosed herein, can tailor copolymer hydrogel membranes toelute the drug at a desired rate. Copolymers can contain, for example,about 15% to about 70% (weight) of HEMA units and from about 85 to 30%(weight) of units of a second ethylenic monomer and possesspredetermined EWC values in the range of from about 20% to about 75%,preferably about 25%. Homogenous copolymers can include those made fromhydrophilic monomeric mixtures containing from about 80% HPMA (weight),and from about 20% HEMA (weight). In further embodiments, the mixturecan further contain a small amount of a polyethylenically unsaturatedcrosslinking agent, e.g., trimethylolpropane trimethacrylate (“TMPTMA”).

Various aspects of the invention include homogeneous hydrophiliccopolymers whose homogeneous polymer structure is formed by thepolymerization of a mixture of hydrophilic monomers describedpreviously; and the drug delivery device that utilizes the homogeneouspolymer cartridges in the delivery system. The polymerization of amixture of hydrophilic monomers and hydrophobic monomers yieldsheterogeneous polymers. Where hydrophobic segments are present in thepolymer, the interfacial free energy increases, thus enhancing proteinadsorption and mineralization after implantation in an animal. Hydrogelsof poly-HEMA, for example, were measured to have interfacial free energyclose to zero. According to the interfacial free energy interpretation,hydrogels of strictly hydrophilic components would strongly appear to bebiocompatible with body tissue. Slightly crosslinked poly-HEMA is ahomogeneous, hydrophilic “homopolymer” (disregarding the relativelysmall quantities of polymerized crosslinking agent therein) ofrelatively fixed characteristics or values. Techniques for altering the“homopolymer” poly-HEMA to impart to it additional characteristics orproperties are difficult, time-consuming, and oftentimes result inerratic property behavior. On the other hand, mixtures of HEMA withvarying quantities of other polymerizable hydrophilic comonomer(s) canbe polymerized to give predictable homogeneous hydrophilic copolymershaving (predetermined) tailor-made properties.

Useful crosslinking agents that can be included in the polymerizablereaction medium include, for example, the polyethylenically unsaturatedcompounds having at least two polymerizable ethylenic sites, such as thedi-, tri- and tetra-ethylenically unsaturated compounds, in particular,the tri-unsaturated crosslinking agents with/without the di-unsaturatedcrosslinking compounds, for example, divinylbenzene, ethylene glycoldimethacrylate and diacrylate, propylene glycol dimethacrylate anddiacrylate; and the di-, tri- and tetra-acrylate or methacrylate estersof the following polyols: triethanolamine, glycerol, pentaerythritol,1,1,1-trimethylolpropane and others.

The polymerization reaction can be carried out in bulk or with an inertsolvent. Suitable solvents include, for example, water; organic solvents(e.g., water-soluble lower aliphatic monohydric alcohols as well aspolyhydric alcohols, e.g., glycol, glycerine, dioxane, etc.; andmixtures thereof).

Compounds useful in the catalysis of the polymerizable ethylenicallyunsaturated compounds include the free-radical compounds and/orinitiators of the type commonly used in vinyl polymerization such as theorganic peroxides, percarbonates, hydrogen peroxides, and alkali metalsulfates. Illustrative examples include cumene hydroperoxide, t-butylhydroperoxide, benzoyl peroxide, bis(4-t-butylcyclohexyl)peroxydicarbonate, hydrogen peroxide, 2,4-dichlorobenzoyl peroxide,acetyl peroxide, di-n-propyl peroxydicarbonate, di-t-butyl peroxide,di-sec-butyl peroxydicarbonate, ammonium sulfate, potassium sulfate, andsodium sulfate. A preferred catalyst is one that is effective atmoderately low temperature such as, for example, at about 20-80° C.(e.g., tert-butyl peroctoate, benzoyl peroxide, and di(secbutyl)peroxydicarbonate).

A conventional redox polymerization catalyst can also be employed.Polymerization of the ethylenic compounds can be effected, for example,using radiation, e.g., ultraviolet, X-Ray, gamma radiation, microwave orother well-known forms of radiation. A preferred catalyst forultraviolet cure is benzoin methyl ether. Catalysts and/or initiatorsand/or radiation are employed in a catalytically-effective amount tooptimize the polymerization reaction.

The current invention focuses on the application of polyurethane basedpolymers, thermoplastics or thermosets, to the creation of implantabledrug devices to deliver biologically active compounds at controlledrates for prolonged period of time. Polyurethane polymers are preferablymade into cylindrical hollow tubes with one or two open ends throughextrusion, (reaction) injection molding, compression molding, orspin-casting (see, e.g., U.S. Pat. Nos. 5,266,325 and 5,292,515, hereinincorporated by reference in their entireties), depending on the type ofpolyurethane used.

Thermoplastic polyurethane can be processed through extrusion, injectionmolding or compression molding. Thermoset polyurethane can be processedthrough reaction injection molding, compression molding or spin-casting.The dimensions of the cylindrical hollow tube are determinable and canbe adjusted precisely.

Polyurethane based polymers are synthesized from multi-functionalpolyols, isocyanates and chain extenders. The characteristics of eachpolyurethane can be attributed to its structure.

Thermoplastic polyurethanes are made of macrodiols, diisocyanates anddifunctional chain extenders (e.g., U.S. Pat. Nos. 4,523,005 and5,254,662, herein incorporated by reference in their entireties).Macrodiols make up the soft domains. Diisocyanates and chain extendersmake up the hard domains. The hard domains serve as physicalcrosslinking sites for the polymers. Varying the ratio of these twodomains can alter the physical characteristics of the polyurethanes.

Thermoset polyurethanes can be made of multifunctional (greater thandifunctional) polyols and/or isocyanates and/or chain extenders (e.g.,U.S. Pat. Nos. 4,386,039 and 4,131,604, herein incorporated by referencein their entireties). Thermoset polyurethanes can also be made byintroducing unsaturated bonds in the polymer chains and appropriatecrosslinkers and/or initiators to do the chemical crosslinking (e.g.,U.S. Pat. No. 4,751,133, herein incorporated by reference in itsentirety). By controlling the amounts of crosslinking sites and how theyare distributed, the release rates of the actives can be controlled.

Different functional groups can be introduced into the polyurethanepolymer chains through the modification of the backbones of polyolsdepending on the properties desired. Where the device is used for thedelivery of water soluble drugs, hydrophilic pendant groups such asionic, carboxyl, ether, and hydroxy groups are incorporated into thepolyols to increase the hydrophilicity of the polymer (e.g., U.S. Pat.Nos. 4,743,673 and 5,354,835, herein incorporated by reference in theirentireties). Where the device is used for the delivery of hydrophobicdrugs, hydrophobic pendant groups such as alkyl, siloxane groups areincorporated into the polyols to increase the hydrophobicity of thepolymer (e.g., U.S. Pat. No. 6,313,254, herein incorporated by referencein its entirety). The release rates of the actives can also becontrolled by the hydrophilicity/hydrophobicity of the polyurethanepolymers.

Small cylindrically-shaped implants of the invention can contain withintheir core, octreotide, preferably octreotide acetate, and optionally, apharmaceutically acceptable carrier. The membrane thickness (between theinterior and exterior surfaces) of the implant is substantially uniform,and serves as a rate-limiting barrier for the release of the containedagent. Such implants can be plasticized or hydrated and reshaped intoother geometrically shaped articles for use in various medicalapplications.

In the manufacture of the implantable formulation, several factors canbe considered. The release profile (delay time, release rate, andduration) is determined; the hydrophilic polymeric material isidentified; and the diffusivity of the active agent through it (as arate-limiting membrane) is measured. The hydration profile of therate-limiting membrane for a given active agent may be readilydetermined by preparing a film of the selected polymer and subjecting itto a diffusion study, using a two compartment vertical glass cell, as iswell known in the art.

The diffusion coefficient and the water content at which diffusionbegins (below which substantially no diffusion occurs—hereinafter “%H_(d)”) are determined. A series of membranes is prepared from variouspolymers. The membranes are then hydrated to their capacity and theirEWCs are measured. The fully hydrated membranes are placed in thetwo-compartment, vertical glass cells to measure and the diffusion ofthe macromolecular composition through the membrane materials at thevarious EWCs is plotted. The equilibrium water content of the mosthydrated membrane through which no diffusion is detected (e.g., none ofthe active agent diffuses into the receptor cell) is the % H_(d) for thesystem being tested. This can be accomplished by plotting a curve of thepermeability versus EWC.

The permeability results (diffusion coefficients) are obtained accordingto Fick's First Law of Diffusion, by use of the equation:

$\frac{Q}{t} = \frac{{APC}_{d}}{1}$

wherein dQ/dt is the flux through the membrane material (μg/hr); it ismeasured as the slope of the linear part of the curve of cumulativetransport versus time; wherein A is the area of the membrane (cm²);wherein P is the membrane's permeability coefficient (cm²/hr), orDK_(d), wherein D is the diffusivity of the membrane (cm²/hr), and K_(d)is the partition coefficient for the membrane/donor solution; wherein 1is the membrane thickness as measured at the end of the experiment (cm);and wherein C_(d) is the concentration of the donor solution (μg/cm³).

The release delay profile can then be determined. Another series ofpolymeric membranes can be prepared, again varying the amounts ofcrosslinker and monomers. These membranes are then hydrated, but onlypartially, e.g., to a water content less than or equal to % H_(d). Thepartially hydrated membranes are placed in two-compartment verticalglass cells to measure and plot the diffusion of the active compoundthrough the membranes versus time. Buffer solutions for the donor andreceptor cells can be selected to contact the partially-hydratedmembranes and further hydrate them at approximately the same rate atwhich they will hydrate in the delivery environment. The time betweencommencement of the diffusion study, i.e., addition of the active agentto the donor cell, and the detection of a pharmaceutically-effectiveconcentration of the active agent in the receptor cell is the releasedelay time for that combination of polymer and initial percenthydration.

To determine the physical dimensions of the cylindrically-shaped device,the total amount of active agent to be delivered is determined. This isthe product of the desired daily dosage and the duration of delivery. Inpreferred embodiments, the duration of delivery is at least about 2months, more preferably about 6 months, and up to about two years. Thedesired daily dosage is, for example, about 10 to about 1000 μg ofoctreotide per day, preferably about 20 to about 800 μg of octreotideper day, more preferably about 30 to about 300 μg of octreotide per day.

The volume of the cylindrical reservoir (core) of a cylindrically-shapeddevice is equal to IIr_(i) ² h wherein r_(i) is the radius of thereservoir and h is its height. The formula for steady state release froma cylinder is:

[dQ/dt]=[2πhDK _(d) C _(d) ]/[In(r _(o) /r _(i))]

wherein r_(o) is the outside radius of the cylindrical device; andwherein C_(d) is the concentration of drug in the donor solution, i.e.,the carrier. Steady state release is obtained when C_(d) is maintainedat saturation. The thickness of the membrane needed for the desiredsustained release is, therefore, r_(o)-r_(i).

The amount of active agent employed will depend not only on the desireddaily dose but also on the number of days that dose level is to bemaintained. While this amount can be calculated empirically, the actualdose delivered is a function of any interaction with materials and thecarrier, if employed in the device.

Once the appropriate polyurethane polymer is chosen, the best method tofabricate the cylindrically shaped implants can be determined by one ofskill in the art to achieve suitable delivery characteristics asdescribed herein.

For thermoplastic polyurethanes, precision extrusion and injectionmolding are can be used to produce two open-end hollow tubes withconsistent physical dimensions. The reservoir can be loaded freely withappropriate formulations containing actives and carriers or filled withpre-fabricated pellets to maximize the loading of the actives. To sealthe two open ends, two pre-fabricated end plugs can be used. The sealingstep can be accomplished through the application of heat or solvent orany other means to seal the ends, preferably permanently.

For thermoset polyurethanes, precision reaction injection molding orspin casting is the preferred choice depending on the curing mechanism.Reaction injection molding is used if the curing mechanism is carriedout through heat and spin casting is used if the curing mechanism iscarried out through light and/or heat. Preferably, hollow tubes with oneopen end are made by spin casting. Preferably, hollow tubes with twoopen ends are made by reaction injection molding. The reservoir can beloaded in the same way as the thermoplastic polyurethanes.

Preferably, to seal an open end, an appropriate light-initiated and/orheat-initiated thermoset polyurethane formulation is used to fill theopen end and this is cured with light and/or heat. More preferably, apre-fabricated end plug can also be used to seal the open end byapplying an appropriate light-initiated and/or heat-initiated thermosetpolyurethane formulation on to the interface between the pre-fabricatedend plug and the open end and cured it with the light and/or heat or anyother means to seal the ends, preferably permanently. The solid activeagent and optional carriers can be compressed into pellet form tomaximize the loading of the actives.

Prior to implantation, the implantable formulations can be optionallyhydrated or “primed” for a predetermined period of time. Priming canenable the active ingredient to begin to infiltrate and saturate thewalls of the hydrogel and potentially begin to leach out of the hydrogelprior to implantation depending upon the amount of time the implant isprimed. A primed implant will begin to release active ingredientsubstantially upon implantation, and may result in a peak release of thedrug shortly after implantation. In contrast, little to no priming mayresult in substantially no release of the active ingredient uponimplantation for a period of time until the implant becomes hydrated andthe active ingredient begins to be released, however these primingcharacteristics depend on the specific formulations being used. Theinvention is directed to, for example, a method of administering acontrolled-release octreotide formulation comprising implanting adehydrated octreotide formulation into a subject.

Depending upon the types of active ingredient, hydrophilic orhydrophobic, the appropriate conditioning and priming media will bechosen. Water based media are preferred for hydrophilic actives and oilbased media are preferred for hydrophobic actives. Alternatively,certain implants of the invention do not need to be primed prior toimplantation. In some instances, priming will improve delivery of theactive agent in a controlled fashion, but in other instances, primingprior to implantation in a subject will not affect delivery in a way tojustify the added time and hassle required for priming the implant.

The hydrating liquid useful in the practice of the invention istypically a liquid simulating the environment in which the activecompound will be released, e.g., body fluid, sterile water, tear fluid,physiological saline solution, phosphate buffer solution and the like.While liquids other than water are useful as the hydrating liquid, thedegree to which a hydrophilic membrane is hydrated is referred to as its“water content.”

The priming and conditioning of the drug delivery devices involves theloading of the actives (drug) into the polymer that surrounds thereservoir, and thus prevent loss of the active before the actual use ofthe implant. The conditions used for the conditioning and priming stepdepend on the active agent, the temperature and the medium in which theyare carried out. The conditions for the conditioning and priming can bethe same in some instances.

The conditioning and priming step in the process of the preparation ofthe drug delivery devices is performed to obtain a determined rate ofrelease of a specific drug. The conditioning and priming step of theimplant containing a hydrophilic drug is preferably carried out in anaqueous medium, more preferably in a saline solution. For hydrophobicdrugs, the medium can be a plasma-like medium, including, but notlimited to, cyclodextrin. The conditioning and priming steps are carriedout by controlling three specific factors, namely the temperature, themedium and the period of time.

A person skilled in the art would understand that the conditioning andpriming step of the drug delivery device will be affected by the mediumin which the device is placed. Histrelin and naltrexone implants, forexample, can be conditioned and primed in saline solution, morespecifically, conditioned in saline solution of 0.9% sodium content andprimed in saline solution of 1.8% sodium chloride content.

The temperature used to condition and prime the drug delivery device canvary across a wide range of temperatures, but, in some instances 37° C.,is used.

The time period used for the conditioning and priming of the drugdelivery devices can vary from about a single day to several weeksdepending on the release rate desired for the specific implant or drug.

A person skilled in the art will understand the steps of conditioningand priming the implants, where appropriate or necessary, is to optimizethe rate of release of the drug contained within the implant. As such, ashorter time period spent on the conditioning and the priming of a drugdelivery device can result, for example, in a lower rate of release ofthe drug compared to a similar drug delivery device that has undergone alonger conditioning and priming step. Without priming, however, it wasunexpectedly found that effective release occurred over a longer periodof time (e.g., 28 weeks and beyond), and lower serum concentrations ofthe active ingredient were found to have ameliorative effects.

The temperature in the conditioning and priming step can also affect therate of release in that a lower temperature results in a lower rate ofrelease of the drug contained in the drug delivery device when comparedto a similar drug delivery device that has undergone a treatment at ahigher temperature.

Similarly, in the case of aqueous solutions, which are in some casespreferably saline solutions, the sodium chloride content of the solutionwill also determine what type of rate of release will be obtained forthe drug delivery device. More specifically, a lower content of sodiumchloride can result in a higher rate of release of drug when compared toa drug delivery device that has undergone a conditioning and primingstep where the sodium chloride content was higher.

To identify the location of the implant, radiopaque material can beincorporated into the delivery device by inserting it into the reservoiror by making it into end plug to be used to seal the cartridge.

The formulation of the present invention can contain a pharmaceuticallyacceptable carrier that can include, for example, suspending media,solvents, aqueous systems and solid substrates or matrices.

Suspending media and solvents useful as the carrier include, forexample, oils such as silicone oil (particularly medical grade), cornoil, castor oil, peanut oil and sesame oil; condensation products ofcastor oil and ethylene oxide; liquid glyceryl triesters of a lowermolecular weight fatty acid; lower alkanols; glycols; and polyalkyleneglycols.

The aqueous systems include, for example, sterile water, saline,dextrose, dextrose in water or saline, and the like. The presence ofelectrolytes in the aqueous systems may tend to lower the solubility ofthe macromolecular drug in them.

The solid substrates or matrices include, for example, starch, gelatin,sugars (e.g., glucose), natural gums (e.g., acacia, sodium alginate,carboxymethyl cellulose), and the like. In a preferred embodiment, thepharmaceutical formulation further comprises about 2% to about 20%, morepreferably about 10% hydroxypropylcellulose. In addition, thepharmaceutical formulations may also contain hydroxyporopylcellulose,hydroxyethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, modified starch or crosslinked polyvinyl pyrrolidone.

The carrier can also contain adjuvants such as preserving, stabilizing,wetting and emulsifying agents and the like.

In one embodiment, a pharmaceutical formulation of the present inventioncomprises a formulation of octreotide acetate within a mixture of HEMAand HPMA copolymer, preferably about 20% HEMA and about 80% HPMA. Thepharmaceutical formulation can comprise, for example, about 20 to about150 milligrams of octreotide, preferably about 40 to about 90milligrams. The formulation can further comprise between about 2 toabout 20% excipients. The formulation can also contain about 10%hydroxypropylcellulose and/or about 2% magnesium stearate.

A pharmaceutical formulation of the present invention can comprise aformulation of about 50 milligrams of octreotide within a mixture ofHEMA and HPMA copolymer, preferably about 20% HEMA and about 80% HPMA.In a further embodiment, the formulation further comprises about 10%hydroxypropylcellulose and 2% magnesium stearate with the octreotideacetate.

A pharmaceutical formulation of the present invention also can comprisea formulation of about 83 mg of octreotide within a mixture of HEMA andHPMA copolymer, preferably about 40% HEMA and about 60% HPMA. In afurther embodiment, the formulation further comprises about 10%hydroxypropylcellulose and 2% magnesium stearate with the octreotideacetate. The pharmaceutical formulations may also contain stearic acid,vegetable stearin, talc and silica.

A pharmaceutical formulation of the present invention can also comprisea formulation of about 20 milligrams to about 150 milligrams, morepreferably about 40 milligrams to about 90 milligrams, of octreotide ina xerogel, preferably a hydrogel or a polyurethane based polymer.

A method of treating a disease associated with a hormonal disorder isprovided. The method can include administering octreotide andmaintaining a plasma concentration at steady state of octreotide betweenabout 0.1 ng/ml and about 9 ng/ml over an extended period of time,preferably at least about two months, and more preferably about sixmonths and up to about two years. In preferred embodiment, the plasmaconcentration at steady state of octreotide is maintained between about1 ng/ml and about 2 ng/ml, more preferably about 1.2 ng/ml to about 1.6ng/ml, over an extended period of time. Hormonal disorders include, forexample, acromegaly.

The invention is also directed to methods for decreasing GH levels byadministering octreotide and maintaining a steady state plasmaconcentration of octreotide between about 0.1 ng/ml and about 9 ng/ml,about 0.5 ng/ml to about 1 ng/ml, about 1 ng/ml to about 2 ng/ml, orabout 1.2 to about 1.6 ng/ml, over an extended period of time,preferably at least about two months, and more preferably about sixmonths, and up to about two years.

The invention is also directed to methods for decreasing IGF-1 levels byadministering octreotide and maintaining a plasma concentration ofoctreotide between about 0.1 ng/ml and about 9 ng/ml, about 0.5 ng/ml toabout 1 ng/ml, about 1 ng/ml to about 2 ng/ml, or about 1.2 to about 1.6ng/ml, over an extended period of time, preferably at least about twomonths, and more preferably about six months, and up to about two years.

The invention is further directed to methods of treating acromegalycomprising administering at least one implant of the present invention,preferably two implants, of the present invention. In the method, eachimplant administered can contain between about 20 to about 150milligrams of octreotide, preferably about 40 to about 90 milligrams ofoctreotide, more preferably about 50 milligrams of octreotide, andrelease a therapeutically effective amount of octreotide over a periodof at least two months, preferably about six months, and up to about twoyears.

The invention is further directed to methods of treating symptomsassociated with carcinoid tumors and VIPomas. Methods of treating severediarrhea and flushing episodes associated with carcinoid tumors byadministering an implantable formulation of octreotide, which releases atherapeutically effective amount of octreotide over at least about twomonths, preferably about six months and up to about two years, are alsoencompassed by the present invention. Methods of treating waterydiarrhea associated with VIPomas by administering an implantableformulation of octreotide, which release a therapeutically effectiveamount of octreotide over at least about two months, preferably aboutsix months and up to about two years, are also encompassed by thepresent invention.

The formulations of the present invention exhibit a specific, desiredrelease profile that maximizes the therapeutic effect while minimizingadverse side effects of the implant. The desired release profile can bedescribed in terms of the maximum plasma concentration of the drug oractive agent (C_(max)) and the plasma concentration of the drug oractive agent at steady state (Css).

The present invention is also directed to therapeutic compositions of ahydrogel and octreotide, wherein, upon implantation, the octreotide isreleased at a rate that provides and/or maintains a Css of about 0.1ng/ml to about 9 ng/ml, about 0.5 ng/ml to about 1 ng/ml, about 1 ng/mlto about 2 ng/ml, or about 1.2 ng/ml to about 1.6 ng/ml. A furtherembodiment is a therapeutic composition of a hydrogel and octreotide,wherein, upon implantation, the octreotide is released at a rate of fromabout 10 μg to about 1000 μg per day over an extended period of time,preferably about 20 μg to about 800 μg, more preferably about 30 μg toabout 300 μg per day. The octreotide can be release over at least abouttwo months, about six months, or up to about two years. The hydrogel cancomprise methacrylate based polymers or polyurethane based polymers.

Another embodiment is a controlled-release formulation comprisingoctreotide and a hydrophilic polymer, which permits release of theoctreotide at a rate of about 30 μg to about 250 μg per day over atleast about two months, about six months or about two years in vitro. Insome embodiment, delivery is about 100 μg to about 130 μg per day. In afurther embodiment, the hydrophilic polymer of the formulation permitsrelease of octreotide at an average rate of about 100 μg per day invitro. The hydrophilic polymer can be selected from polyurethane basedpolymers and methacrylate based polymers.

A further embodiment of the present invention is a controlled-releaseformulation comprising octreotide for implantation, wherein theformulation comprises octreotide in a hydrophilic polymer effective topermit in vitro release of no more than about 20% of said octreotidefrom the formulation after about 6 weeks; and about 60% of saidoctreotide from said formulation after about six months.

The amount of a pharmaceutically-acceptable octreotide (e.g., varioussalts, salvation states, or prodrugs thereof) included in thepharmaceutical composition of the present invention will vary dependingupon a variety of factors, including, for example, the specificoctreotide used, the desired dosage level, the type and amount ofhydrogel used, and the presence, types and amounts of additionalmaterials included in the composition. The amount of octreotide, or aderivative thereof, in the formulation varies depending on the desireddose for efficient drug delivery, the molecular weight, and the activityof the compound. The actual amount of the used drug can depend on apatient's age, weight, sex, medical condition, disease or any othermedical criteria. The actual drug amount is determined according tointended medical use by techniques known in the art. The pharmaceuticaldosage formulated according to the invention can be administered, forexample, about once every six months as determined by the attendingphysician.

The octreotide typically is formulated in the implant or otherpharmaceutical composition in amounts of about 20 milligrams to about150 milligrams, preferably about 40 to about 90 milligrams ofoctreotide, more preferably about 50 to about 85 milligrams. For adults,the daily dose for treatment of acromegaly is typically about 300 μg toabout 600 μg of immediate release octreotide per day (100 μg or 200 μgSandostatin®). The amount of octreotide in the composition can beselected, for example, to release from about 10 μg to about 1000 μg perday over an extended period of time, about 20 μg to about 800 μg perday, or about 30 μg to about 300 μg per day. Such release rates maintaindesired therapeutic levels in a patient's blood at about 0.1 to about 9ng/ml over an extended period of time.

The hydrogel device in which octreotide is contained provides acontrolled-release of octreotide into the plasma of the patient.Hydrogels suitable for controlling the release rate of octreotide foruse in the pharmaceutical compositions of the present invention includepolymers of hydrophilic monomers, including, but not limited to HPMA,HEMA and the like. Such hydrogels are also capable of preventingdegradation and loss of octreotide from the composition.

IA pharmaceutical formulation of the present invention can compriseoctreotide acetate within a hydrophilic copolymer of 2-hydroxyethylmethacrylate and hydroxypropyl methacrylate. The copolymer of thepharmaceutical formulation can comprise, for example, about 20% HEMA andabout 80% HPMA. The copolymer of the pharmaceutical formulation canalternatively comprise, for example, about 40% HEMA and about 60% HPMA.

The size, shape and surface area of the implant can be modified toincrease or decrease the release rate of octreotide from the implant.

The pharmaceutical composition of the present invention can include alsoauxiliary agents or excipients, for example, glidants, dissolutionagents, surfactants, diluents, binders including low temperature meltingbinders, disintegrants and/or lubricants. Dissolution agents increasethe dissolution rate of octreotide from the dosage formulation and canfunction by increasing the solubility of octreotide. Suitabledissolution agents include, for example, organic acids such as citricacid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, aceticacid, malic acid, glutaric acid and adipic acid, which can be used aloneor in combination. These agents man also be combined with salts of theacids, e.g., sodium citrate with citric acid, to produce a buffersystem.

Other agents that can alter the pH of the microenvironment ondissolution and establishment of a therapeutically-effective plasmaconcentration profile of octreotide include salts of inorganic acids andmagnesium hydroxide. Other agents that can be used are surfactants andother solubilizing materials. Surfactants that are suitable for use inthe pharmaceutical composition of the present invention include, forexample, sodium lauryl sulfate, polyethylene stearates, polyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives,polyoxyethylene alkyl ethers, benzyl benzoate, cetrimide, cetyl alcohol,docusate sodium, glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, lecithin, medium chain triglycerides, monoethanolamine,oleic acid, poloxamers, polyvinyl alcohol and sorbitan fatty acidesters.

Diluents that are suitable for use in the pharmaceutical composition ofthe present invention include, for example, pharmaceutically acceptableinert fillers such as microcrystalline cellulose, lactose, sucrose,fructose, glucose dextrose, or other sugars, dibasic calcium phosphate,calcium sulfate, cellulose, ethylcellulose, cellulose derivatives,kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugaralcohols, dry starch, saccharides, dextrin, maltodextrin or otherpolysaccharides, inositol or mixtures thereof. The diluent can be awater-soluble diluent. Examples of diluents include, for example:microcrystalline cellulose such as Avicel PH112, Avicel PH101 and AvicelPH102 available from FMC Corporation; lactose such as lactosemonohydrate, lactose anhydrous, and Pharmatose DCL 21; dibasic calciumphosphate such as Emcompress available from Penwest Pharmaceuticals;mannitol; starch; sorbitol; sucrose; and glucose. Diluents are carefullyselected to match the specific composition with attention paid to thecompression properties. The diluent is preferably used in an amount ofabout 2% to about 80% by weight, preferably about 20% to about 50% byweight, of the controlled-release composition.

Glidants are used to improve the flow and compressibility of ingredientsduring processing. Suitable glidants include, for example, colloidalsilicon dioxide, a sub-micron fumed silica that can be prepared, forexample, by vapor-phase hydrolysis of a silicon compound such as, forexample, silicon tetrachloride. Colloidal silicon dioxide is asub-micron amorphous powder that is commercially available from a numberof sources, including Cabot Corporation (under the trade nameCab-O-Sil®); Degussa, Inc. (under the trade name Aerosil®); and E.I.DuPont & Co. Colloidal silicon dioxide is also known as colloidalsilica, fumed silica, light anhydrous silicic acid, silicic anhydrideand silicon dioxide fumed, among others. In one embodiment, the glidantcomprises Aerosil® 200.

Disintegrants that are suitable for use in the pharmaceuticalcomposition of the present invention include, for example, starches,sodium starch glycolate, crospovidone, croscarmellose, microcrystallinecellulose, low substituted hydroxypropyl cellulose, pectins, potassiummethacrylate-divinylbenzene copolymer, poly(vinyl alcohol), thylamide,sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, betacyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite andmixtures thereof.

The active ingredient of the present invention can be mixed withexcipients that are pharmaceutically-acceptable and compatible with theactive ingredient and in amounts suitable for use in the therapeuticmethods described herein. Various excipients can be homogeneously mixedwith octreotide of the present invention as would be known to thoseskilled in the art. Octreotide, for example, can be mixed or combinedwith excipients such as but not limited to microcrystalline cellulose,colloidal silicon dioxide, lactose, starch, sorbitol, cyclodextrin andcombinations of these.

Lubricants that are suitable for use in the pharmaceutical compositionof the present invention include agents that act on the flowability ofthe powder to be compressed include but are not limited to silicondioxide such as, for example, Aerosil® 200, talc; stearic acid,magnesium stearate, calcium stearate, hydrogenated vegetable oils,sodium benzoate, sodium chloride, leucine carbowax, magnesium laurylsulfate, and glyceryl monostearate.

The invention is further directed to a controlled-release implantabledosage formulation that includes an effective amount a octreotide in ahydrogel, and that, upon administration to a patient or as part of atherapy regimen, provides a release profile (oftherapeutically-effective blood plasma level of octreotide) extendingfor a period of at least about two months, about six months or up toabout two years.

The dosage formulation of the present invention can comprise one or morepharmaceutically-acceptable excipients. In preferred embodiments, thedosage formulation will comprise diluents and a lubricant in addition tooctreotide unit dose and the rate-controlling polymer. For this purpose,magnesium stearate is a suitable excipient. When these materials areused, the magnesium stearate component can comprise from about 0.5 toabout 5% w/w of the dosage formulation (e.g., about 2%), and thehydrogel and octreotide comprise the remainder of the formulation.

Another suitable excipient is hydroxypropylcellulose. When used, thehydroxypropylcellulose component can comprise from about 0.5 to about20% w/w of the dosage formulation (e.g., about 10%), and the hydrogeland octreotide comprise the remainder of the formulation.

In one embodiment, the formulation comprises both magnesium stearate andhydroxypropylcellulose, preferably about 2% magnesium stearate and about10% hydroxypropylcellulose and the hydrogel and octreotide comprise theremainder of the formulation.

The compositions of the present invention can be used for the treatmentof hormonal diseases, e.g., acromegaly, or symptoms thereofcharacterized by increased levels of GH and IGF-1 by administering to apatient an implantable formulation of the present invention. The implantcan be administered, for example, every about six months, and release atherapeutically-effective amount of octreotide. The implantablecomposition releases a concentration of octreotide in the patient atabout the minimum therapeutically-effective level to ameliorate thehormonal disorder, yet relatively lower compared to the maximumconcentration to enhance restful periods for the patient during the day.The compositions can be administered to a subject at a dose and for aperiod sufficient to allow the subject to tolerate the dose withoutshowing adverse effects and thereafter increasing the dose of the activeagent, if needed, at selected intervals of time until a therapeutic doseis achieved in the subject. The active agent can be administered, forexample, at a dose of from about 10 μg to about 1000 μg, about 20 μg toabout 800 μg, or about 30 μg to about 300 μg, of octreotide daily for aperiod of at least about two months, about six months, or up to abouttwo years.

Compositions of the present invention where the octreotide is octreotideacetate are suitable for use in the treatment of hormonal disorders thatare characterized by increased levels of GH and IGF-1, e.g., acromegaly.The octreotide acetate agent in accordance with the invention is alsosuitable for the treatment of symptoms associated with carcinoidsyndrome and VIPomas.

Additional features and embodiments of the present invention areillustrated by the following non-limiting examples.

EXEMPLIFICATION Example 1 In Vitro Octreotide Release Rates

This example illustrates preparation of implantable octreotideformulations of the present invention and their in vitro release ofoctreotide. In the present study, a series of implants were tested todetermine stability and in vitro release characteristics of octreotidefrom the hydrogel formulations over about 22 weeks (No. 146), 28 weeks(No. 136) and 33 weeks (all other formulations). Each implant containedabout 50 milligrams of octreotide acetate and about 2% stearic acid, butthe polymer cartridges contained different amounts of HEMA and HPMA andtherefore exhibited different % EWCs, as depicted in Table 1.

TABLE 1 Formulation % % % Number HEMA HPMA EWC Excipients/OtherIngredients 146 0 99.5 22.9 2% stearic acid 145 10 89.5 23.4 2% stearicacid 147 15 84.5 24.4 2% stearic acid 133 20 79.5 25.2 2% stearic acid144 25 74.5 25.6 2% stearic acid 143 30 69.5 26.1 2% stearic acid 142 3564.5 26.6 2% stearic acid 136 40 59.5 27.6 2% stearic acid

FIGS. 2, 3 and 4 depict the release of octreotide from the implant perday for each of the formulations provided above. As noted in FIG. 2, theinitial release was relatively high and dropped relatively quickly forFormulation No. 136. As shown in FIG. 3, the initial release rate forFormulation No. 146 was relatively low. FIG. 4 presents the releaseprofiles for Formulation Nos: 145, 147, 133, 144, 143 and 142. As shownin FIG. 4, the initial release rates show a good relationship with the %EWC, ranging from 20 to 450 μg per day for % EWCs of 22.9 to 27.6%.Problems were encountered, however, with respect to the osmotic pressuredifferential within the implant and the elution media. To stabilize theoctreotide formulations, a number of experiments were designed usingexcipients that would provide better stability based on a “preferentialhydration” principle.

Example 2 Formulation Study in Calf Serum

To determine the effect of osmotic pressure on the swelling problem twoimplants of the present invention corresponding to Formulation No. 136and Formulation No. 143 were eluted in calf serum. In particular,Formulation No. 136, composed of about 40% HEMA and 60% HPMA, containingoctreotide acetate with 2% stearic acid and Formulation No. 143,composed of about 30% HEMA and 70% HPMA, containing a mixture of 20%PEG3300 and 80% octreotide acetate, were tested. After three months, theimplants exhibited normal appearance, being relatively straight and onlyslightly swollen.

Example 3 Formulation Study

Due to osmotic pressure differential, the implants described in Example1 were seen to swell significantly—ultimately resulting in bursting ofthe implants. This example illustrates formulations designed to screenagents useful in stabilization of the octreotide implant. A series ofimplants was monitored to determine the effect of excipient on implantshape and durability. Each of the polymer cartridges was composed ofabout 28% HEMA, about 66.5% HPMA and 5% glycerin. The contents containedoctreotide acetate with various excipients, as shown in Table 2.

TABLE 2 Sample No. Excipients/Other Ingredients 1 None 2 20% PEG 3300 340% PEG 3300 4  2% Stearic acid (control) 5 10% Glycolic acid 6 20%Poly(lactic acid) 7 10% Mannitol 8 10% MCC (microcrystalline cellulose)9 20% MCC 10 10% Sesame oil

Hydrophobic agents such as sesame oil and MCC separated in theformulation and did not provide “preferential hydration” and were lesspreferable in accordance with the present invention. Hydrophilic agentslike PEG 3300 increased the osmotic pressure differential and increasedswelling. Low molecular weight additives like mannitol and glycolic aciddid not provide a stabilizing effect and resulted in a decrease inintegrity. None of these agents provided satisfactory stabilization ofthe octreotide formulations.

Example 4 Formulation Study and In Vitro Octreotide Release Rates

This study was conducted to evaluate stability of octreotide in hydrogelimplants using various excipients as shown in Table 3. The excipientswere chosen to have high molecular weight and some hydrophilic nature.Each implant was made from polymer cartridges composed of about 20% HEMAand about 80% HPMA. The appearance of the implants in saline wasmonitored and rated over the course of nine weeks. The results are shownin Table 3.

TABLE 3 Implant Appearance Formulation at 9 Weeks No. Excipients/OtherIngredients (see key below) 133 20% Dextran 3 133 20% TPGS (vitamin Ederivative) 2 133 20% HEC (hydroxyethyl cellulose) 3 133 20% HPC(hydroxypropyl cellulose) 2 133 20% Albumin 2 133 20% Pectin 2 133 20%AcDiSol 1.5 133 20% Carbopol 1 133  2% SA (stearic acid) - control 4

As depicted in FIG. 5, the formulation containing dextran had thehighest elution rate. The formulations containing pectin, AcDiSol andCarbopol exhibited less than satisfactory release after two weekshydration and nine weeks elution. Accordingly, a preferred embodimenthaving superior stabilizing effect, combination of good elution andappearance, was achieved with hydroxypropyl cellulose.

Example 5 One-Month Implantation Study in a Healthy Dog

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically-acceptablesalts thereof A healthy dog was implanted with one octreotide subdermalimplant of the present invention. The octreotide subdermal implantformulation had a water content of 26.6%, containing 44 mg octreotideacetate. In vitro release rates were estimated at about 500 μg/day inweek 1 and decreasing to about 300 μg/day in week 4 for a total releaseof about 10 mg of octreotide over the duration of the study. The implantwas removed at 28 days after implantation. The implant used in thisstudy was about 3.5 cm in length. Blood samples (1.5 ml) to obtain theserum concentration of octreotide acetate, IGF-1 and GH were obtained ondays 0, 1-7, 11, 14, 18, 21, 25 and 28 by jugular puncture withoutanesthesia and without fasting.

Clinical observations included that the octreotide implant formulationwas well-tolerated, food intake was normal, and no abnormal behavior wasnoted.

Serum analysis showed a peak of octreotide acetate at day 4 anddetectable amounts of octreotide acetate at all intervals measured.IGF-1 concentrations decreased after implantation until day 4, thenreturned to pre-dose levels by day 25. IGF-1 levels declined from 40 to90% of pre-implantation level, as can be seen in FIG. 6.

Example 6 Six-Month Implantation Study in Six Healthy Dogs

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically-acceptablesalts thereof. Six healthy dogs were divided into two groups andimplanted with one or two octreotide subdermal implants of the presentinvention, respectively. The octreotide subdermal implants had a watercontent of about 25.2% and contained about 60 mg octreotide acetate. Theimplants were removed six months after implantation. Blood samples (10ml) to obtain the serum concentration of octreotide acetate, IGF-1 andGH were obtained once daily for the first 7 days following implantationfollowed by twice a week sampling for three weeks, and then once a weekuntil conclusion of the six month period. Four days prior toimplantation, baseline serum samples were taken as a control.

Results indicate octreotide serum levels ranged from 200 to 700 μg/ml indogs receiving one implant and 400 to 1000 μg/ml in dogs receiving twoimplants. IGF-1 levels were reduced as much as 90% in both treatmentgroups as can be seen in FIGS. 7 and 8. Measurement of serum GH levelswas abandoned after about the first month of the study because levels inhealthy animals are too low to detect further reductions. Clinicalobservations included the octreotide implant formulation waswell-tolerated, food intake was normal, and no abnormal behavior wasnoted.

Example 7 Six-Month Implantation Study in Humans

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. A six-month study was conducted in eleven patients withacromegaly. One or two implants of the present invention were implantedsubcutaneously in 11 patients diagnosed with acromegaly, who werepreviously treated with a commercially-available octreotide LARformulation. Levels of GH and IGF-1 were measured at baseline and everymonth thereafter for a period of six months. Each implant containedapproximately 60 mg of octreotide acetate in a copolymer of 20% HEMA and79.5% HPMA, with an EWC of about 25.2%. The implants used in this studywere about 44 mm in length in a dry state and 50 mm in length in ahydrated state. The diameters of the implants were about 2.8 mm in a drystate and about 3.5 to about 3.6 mm in a hydrated state. The implantswere hydrated for a period of about 1 week prior to implantation.

The reference ranges for GH is up to 2.5 mg/L, age-independent. Table 4illustrates the basal levels of GH in mg/L over six months afterimplantation of octreotide implants of the present invention. PatientNo. 11 did not participate in the study due to failure to meet screeningcriteria.

TABLE 4 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 #(Insertion) (Month 1) (Month 2) (Month 3) (Month 4) (Month 5) (Month 6)Implants Screening GH Basal GH Basal GH Basal GH Basal GH Basal GH BasalGH Basal GH Patient Age Rec'd (mg/L) (mg/L) (mg/L) (mg/L) (mg/L) (mg/L)(mg/L) (mg/L) 001 39 1 26 16.3 0.9 1.5 1.1 1.1 1.1 2.1 002 38 2 17.820.7 1.4 0.2 0.3 0.2 0.3 0.48 003 49 1 67 55 2.8 3.1 3.3 5.0 5.3 5.8 00447 2 7.9 7 2.6 3.8 2.8 3.7 4.0 2.4 005 43 1 10.8 11 2.2 1.8 2.2 1.6 2.21.3 006 43 1 1.7 1.7 1.8 2.3 1.9 1.7 1.8 1.9 007 30 2 23.3 21.8 2.4 2.22.9 2.0 1.1 0.51 008 58 2 1.9 3.2 0.1 0.1 2.0 0.1 0.6 0.11 009 47 2 14.914.1 1.4 0.9 1.5 1.1 1.4 1.4 010 78 1 4 5.2 0.4 0.2 0.5 0.2 0.3 1.0 01240 2 21.1 27.8 13.5 13.7 14 11.9 8.9 13.1 mean 16.7 2.7 2.7 3.0 2.6 2.72.7

As shown above, by month six 89% of subjects exhibited normalized growthhormone levels. Reference ranges for IGF-1 are as follows: (i) 17-24years old about 180-780 ng/mL; (ii) 25-39 years old about 114-400 ng/mL;(iii) 40-54 years old about 90-360 ng/mL; and (iv)>54 years old about70-290 ng/mL.

Table 5 illustrates the basal levels of IGF-1 in ng/ml over six monthsafter implantation of octreotide implants of the present invention.

TABLE 5 Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 #Screening (Insertion) (Month 1) (Month 2) (Month 3) (Month 4) (Month 5)(Month 6) Implants IGF-1 IGF-1 IGF-1 IGF-1 IGF-1 IGF-1 IGF-1 IGF-1Patient Age Rec'd (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL) (ng/mL)(ng/mL) (ng/mL) 001 39 1 1500 1500 820 600 900 880 790 750 002 38 2 17001300 210 180 190 170 130 230 003 49 1 1100 1200 610 550 750 660 850 660004 47 2 1700 1800 1100 1200 1200 1100 910 990 005 43 1 1100 1000 450510 480 600 490 430 006 43 1 520 580 470 430 440 480 440 460 007 30 21900 1700 440 560 560 600 430 520 008 58 2 1700 1200 220 240 170 260 160240 009 47 2 2200 1800 590 830 950 930 1100 1100 010 78 1 590 490 270260 230 310 220 350 012 40 2 1600 1600 1300 1500 1400 1700 1500 1400mean 1288 589 624 661 699 602 648

As shown above, by month six, 22% of subjects exhibited a normalizedIGF-1 level.

FIGS. 9A and 9B demonstrate a comparison of the octreotide implant ofthe present invention with a commercially-available formulation ofoctreotide acetate. The efficacy of the implant appeared to be at leastas good as that of the commercially-available octreotide LARformulation. The therapeutic effect of these implants continuedsuccessfully for the entire 6 months of the study duration.

IGF-1 levels were decreased in all patients, with normalization in 2patients. The decrease was already observed at one month of therapy andthe mean IGF-1 level was stable for the following 5 months. A comparisonwith decreases previously observed in the same patients while on thecommercially available octreotide LAR formulation therapy was possiblein 8 of the 9 patients. In 6 of the 8 patients, the percentage decreasein IGF-1 during the implant was greater than that while on thecommercially-available octreotide LAR formulation, whereas in 2, it wasless. After 6 months of therapy with the implant, GH levels in 3patients were <1 ng/ml and in another 5, were <2.5 ng/ml. This comparedfavorably with the results on the commercially-available octreotide LARformulation, where GH levels in only 2 patients were <1 ng/ml and inanother 2, were under 2.5 ng/ml.

Levels of octreotide in the serum of patients was also measured, asshown in Table 6.

TABLE 6 Month 1 2 3 4 5 6 7 #Implants Patient ID Visit 2 Visit 3 Visit 4Visit 5 Visit 6 Visit 7 Visit 8 Gender 1 Patient 1 1181 874.5 738.0894.3 699.2 722.3 169.0 F 2 Patient 2 2686 2478 1625 1833 1388 1203 280M 1 Patient 3 2570 2351 1332 980.5 1131 775.2 173 F 2 Patient 4 42683308 2582 2650 2455 1984 166 M 1 Patient 5 1218 1022 610.0 783.2 709.4545.8 144 F 1 Patient 6 1899 1445 1427 1123 1148 747.7 206 F 2 Patient 75524 2621 3656 3141 2205 1466 154 F 2 Patient 8 8684 3387 4899 3336 34541765 170 F 2 Patient 9 3850 860.6 2638 1766 1729 1510 203 M 1 Patient 102055 1628 1192 863.9 1641 1231 1130 F 2 Patient 12 2527 1366 2006 962.81484 1156 189 M

A comparison of the octreotide levels achieved with one and two implantsis depicted in the graph in FIG. 10. Overall, results indicated that theoctreotide implant of the present invention is at least as effective asthe commercially available LAR formulation of octreotide acetate inreducing GH levels and IGF-1 levels in patients with acromegaly.

Example 8 In Vitro Octreotide Delivery Using Dry Implants

This example illustrates preparation of formulations of the presentinvention and their release of octreotide or pharmaceutically acceptablesalts thereof. Two healthy dogs were implanted with one octreotidesubdermal implant of the present invention. The implants were nothydrated prior to implantation. The octreotide subdermal implants werecomposed of about 59.5% HPMA and about 40% HEMA and had an equilibriumwater content of about 27.6%. The implants contained about 84 mg ofoctreotide acetate, hydroxypropylcellulose and magnesium stearate. Theimplants were removed six months after implantation. Blood samples (10ml) were drawn to obtain the serum concentration of octreotide acetateand IGF-1 once daily every other day for the first four weeks followingimplantation followed by twice a week sampling for four weeks, and thenonce a week until conclusion of the six month period. Two days prior toimplantation, baseline serum samples were taken as a control.

FIG. 11 shows the octreotide levels in the serum of the dogs and FIG. 12shows the levels of IGF-1 in the dogs.

Example 9 Implant Compositions

Possible compositions for the implants of the invention include, forexample, those listed in Table 7, below. Implant cartridges greater thanabout 3.2-3.4 mm (dry) are aided by the use of release agents, e.g.,vitamin E TPGS, during the formation process.

TABLE 7 Composition of Implant Small Implant Large Implant API 60 mgOctreotide Acetate 84 mg Octreotide Acetate Pellet Excipients 10%Hydroxypropyl 10% Hydroxypropyl cellulose (~6.8 mg/ cellulose (~9.5 mg/implant) implant) 2% Magnesium Stearate 2% Magnesium Stearate (~1.3mg/implant) (~2 mg/implant) Monomer 20% HEMA 40% HEMA Mixture 79.5% HPMA59.5% HPMA Composition 0.5% TMPTMA 0.5% TMPTMA Added to mixture: Addedto mixture: 1% Triton X-100 1% Vitamin E TPGS 0.3% BME 0.3% BME 0.1%P-16 0.1% P-16 Dry Implant Size 2.8 mm × 43 mm 3.4 mm × 43 mm SurfaceArea 378 mm² 459 mm² Hydrated Implant 3.4 mm × 50 mm 4.3 mm × 50 mm SizeSurface Area 534 mm² 675 mm² EWC 26.0% 28.7% Sterilization GammaIrradiation Gamma Irradiation Packaging Implants packaged dry in 2Implants packaged dry in Solution compartment package with 2 compartmentpackage 0.9% saline solution in the with second compartment. 0.9% salinesolution in Implant is combined with the second compartment. saline 7-14days prior to Implant is combined with implantation to allow for saline3-7 days prior to implant hydration. implantation to allow for implanthydration. Packaging Divided Pouch with Divided Pouch with LF4835W FoilJT48FLLP Foil Barrier/FR5500 PET/PE Barrier/IT-CB259B Clear Sleeve asAluminum Oxide CTD components. LF4835W - PET Clear Sleeve as DMF # 15796components. FR5500 - Approved for For use in sterile medical foodcontact packaging Average Daily 130 μg/day for 6 months 250 μg/day for 6months Release Rate

Example 10 An Open-Label Study to the Evaluate the Pharmacokinetic andPharmacodynamic Response of a Hydrated and Non-Hydrated 84 mg OctreotideImplant in Patients with Acromegaly

Approximately 30 patients with acromegaly were enrolled after writteninformed consent was obtained. Patients were divided in 2 groups per thestudy randomization schedule: 15 patients received one hydrated 84 mgoctreotide implant and 15 patients received one non-hydrated 84 mgoctreotide implant. Eligible patients received the implant within 7 daysof their screening visit. The octreotide implant was insertedsubcutaneously in the inner aspect of their non-dominant arm under localanesthesia. Blood samples for the determination of IGF-1, GH andoctreotide serum concentrations were collected at predetermined timepoints within the first 6 weeks after implantation. Patients then returnfor visits at Week 8, 12, 16, 20 and 24 to have blood samples collectedfor the determination of IGF-1, GH and octreotide serum concentrations,as well as safety assessments. At the end of the 6-month (24-week)treatment phase, the implant will be removed. Following implant removal,the patient will be instructed to return in 4 weeks for the End of StudyVisit (Week 28). Safety and efficacy will be carefully monitoredthroughout the study.

Investigational Products:

-   -   Hydrated octreotide implant (84 mg octreotide acetate) for        subcutaneous implantation    -   Non-hydrated octreotide implant (84 mg octreotide acetate) for        subcutaneous implantation

Duration of Treatment:

Eligible patients receive one implant, either hydrated or non-hydrated.At the end of the 6-month (24-week) treatment phase, the implant will beremoved. Following implant removal, the patient will be instructed toreturn in 4 weeks for the End of Study Visit.

Criteria for Inclusion:

-   -   1. Male and female patients with acromegaly    -   2. Must be ≧18 years of age    -   3. Confirmed diagnosis of a growth hormone-secreting tumor        (elevation of IGF-1 level ≧20% above upper limit of age- and        sex-adjusted normal value and either a post-glucose GH of ≧1.0        ng/ml or a pituitary tumor demonstrable on MRI). If patient has        undergone pituitary surgery and has residual tumor present, it        must be at least 3 mm in distance from the optic chiasm (unless        patient is not a surgical candidate) and IGF-1 level must be        elevated as described above. If no residual tumor is present or        patient is inoperable then patient must meet both IGF-1 and GH        criteria as described above.    -   4. Must be either a full or partial responder to octreotide        demonstrated by historical laboratory values, as defined below:        -   a. Full responder: suppression of serum IGF-1 to normal age-            and sex-adjusted levels and suppression of serum GH to <1.0            ng/ml after OGTT        -   b. Partial responder: a ≧30% decrease in IGF-1 and GH values            when compared to pre-treatment values, but not meeting            criteria for full responder        -   c. OR        -   d. Must be a responder to octreotide demonstrated by            laboratory values obtained via an acute aqueous test during            the Screening Visit for octreotide naïve patients or            patients in whom response to octreotide is unknown, as            defined below:        -   e. Responder via acute aqueous test: a ≧30% decrease in GH            values at any time point of the 4 hour test period in            response to a subcutaneous injection of 100 μg of aqueous            octreotide    -   5. Must be able to communicate, provide written informed        consent, and willing to participate and comply with study        requirements    -   6. Patient is eligible to participate in the opinion of the        Investigator

Criteria for Exclusion:

-   -   1. Women who are pregnant, lactating, or of child-bearing        potential who are not practicing a medically acceptable method        of birth control    -   2. Patients with pituitary surgery less than 12 weeks prior to        screening    -   3. Patients with liver disease (e.g., cirrhosis, chronic active        or persistent hepatitis or persistent abnormalities of ALT, AST        (level >2× normal), alkaline phosphatase (level >2× normal), or        direct bilirubin (level >1.5× normal)    -   4. Other laboratory values considered by the Investigator or        Sponsor to be clinically significant    -   5. Patients with unstable angina, sustained ventricular        arrhythmias, heart failure (NYHA III and IV), or a history of an        acute myocardial infarction within 3 months of screening    -   6. Patients with symptomatic cholelithiasis    -   7. Patients with a history of drug or alcohol abuse within 6        months of screening    -   8. Patients who have received any investigational drug within 1        month of screening    -   9. Patients receiving radiotherapy for their pituitary tumor at        any time before screening    -   10. Patients who have discontinued octreotide due to        tolerability or efficacy issues.

Serum levels of octreotide were determined (see FIGS. 13 and 14 forgraphical data).

The efficacy of cytokine concentration modulation after the octreotideimplant was inserted, either in the dry form or after hydration, isshown in FIGS. 15, 16, and 17.

Example 11 Treatment of Tumors with Octreotide

Sandostatin LAR® Depot, as indicated on the FDA label (the entirecontents of which are herein incorporated by reference), is along-acting dosage form consisting of microspheres of the biodegradableglucose star polymer, D,L-lactic and glycolic acids copolymer,containing octreotide. It maintains all of the clinical andpharmacological characteristics of the immediate-release dosage formSandostatin® (octreotide acetate) Injection with the added feature ofslow release of octreotide from the site of injection, reducing the needfor frequent administration. This slow release occurs as the polymerbiodegrades, primarily through hydrolysis. Sandostatin LAR®Depot isdesigned to be injected intramuscularly (intragluteally) once every fourweeks.

Octreotide exerts pharmacologic actions similar to the natural hormone,somatostatin. It is an even more potent inhibitor of growth hormone,glucagon, and insulin than somatostatin. Like somatostatin, it alsosuppresses LH response to GnRH, decreases splanchnic blood flow, andinhibits release of serotonin, gastrin, vasoactive intestinal peptide,secretin, motilin, and pancreatic polypeptide. By virtue of thesepharmacological actions, octreotide has been used to treat the symptomsassociated with, for example, metastatic carcinoid tumors (flushing anddiarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas(watery diarrhea). Octreotide substantially reduces and in many casescan normalize growth hormone and/or IGF-I (somatomedin C) levels inpatients with acromegaly. Single doses of Sandostatin® Injection givensubcutaneously have been shown to inhibit gallbladder contractility andto decrease bile secretion in normal volunteers.

In patients with acromegaly, the pharmacokinetics differ somewhat fromthose in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volumeof distribution (Vdss) was estimated to be 21.6±8.5 L and the total bodyclearance was increased to 18 L/h. The mean percent of the drug boundwas 41.2%. The disposition and elimination half-lives were similar tonormals.

Treating these tumors typically involves surgery as the first-linetherapy. Failing surgery, patients are usually given octreotideinjections (such as S-Lar). Chemotherapy may also prove beneficial—anddoes so in about 30% of patients. Patients with carcinoid tumors weretreated with six doses of S-Lar at 10, 20, or 30 mg given by i.m.injection every 4 weeks. Resulting serum concentrations were 1.2, 2.5,and 4.2 ng/mL. Steady state was achieved after two doses at 20 or 30 mgand after 3 doses at 10 mg.

Treatment with S-Lar reduced daily stool frequency to 2-2.5 stools/day,decreased mean daily flushing episodes to 0.5 to 1 episode/day, andreduced median 24-hr urinary 5-HIAA levels by 38-50%. It should be notedthat over a 6 m trial, 50-70% of patients who completed the trialrequired supplemental Sandostatin injections to help controlexacerbation of symptoms.

Although the present invention has been described in considerable detailwith reference to certain preferred embodiments thereof, other versionsare possible. Therefore the spirit and scope of the appended claimsshould not be limited to the description and the preferred versionscontained within this specification.

1. A method of delivering octreotide to a subject with a substantiallyzero-order release profile over an extended period of time, but no lessthan about six months, the method comprising: subcutaneously implantingin the subject at least one implantable device; wherein: the at leastone implantable device comprises a composition comprising octreotideencased in a hydrophilic polymer; and the implantable device isimplanted in a dry state, such that the subject receives on a dailybasis over a period of at least about six months dose amounts ofoctreotide, which are effective to treat the subject.
 2. The method ofclaim 1, wherein the hydrophilic polymer comprises a co-polymer obtainedfrom the co-polymerization of a mixture comprising at least twohydrophilic, ethylenically unsaturated monomers
 3. The method of claim1, wherein the hydrophilic polymer comprises one or moremethacrylate-based polymers.
 4. The method of claim 1, wherein thehydrophilic polymer comprises a hydrophilic polyurethane.
 5. The methodof claim 1, wherein the octreotide is in free form, salt form or in theform of a complex thereof.
 6. The method of claim 1, wherein theoctreotide is octreotide acetate.
 7. The method of claim 1, wherein thesubject is afflicted with a GH or IGF-1 hormone disorder or itssymptoms.
 8. The method of claim 7, wherein the GH or IGF-1 disorder isacromegaly.
 9. The method of claim 1, wherein the subject receivesoctreotide at an average rate ranging from about 75 μg per day to about300 μg per day over a period of at least about six months.
 10. Themethod of claim 1, wherein the dose amounts of octreotide received bythe subject result in octreotide serum levels ranging from about 0.5ng/ml to about 2 ng/ml.
 11. The method of claim 1, wherein the subjectreceives an effective amount of octreotide for a period of at leastabout twelve months.
 12. The method of claim 1, wherein the dose amountsof octreotide received by the subject result in octreotide serum levelsranging from about 0.8 ng/ml to about 1.8 ng/ml.
 13. The method of claim1, wherein the dose amounts of octreotide received by the subject resultin C_(max) for octreotide serum levels below about 1.3 ng/ml.
 14. Themethod of claim 1, wherein the dose amounts of octreotide received bythe subject result in C_(max) for octreotide serum levels below about1.0 ng/ml.
 15. The method of claim 1, wherein release of octreotideoccurs at least three to about ten days after implantation.
 16. Themethod of claim 1, wherein the subject is afflicted with a conditionselected from the group consisting of carcinoid syndrome, VIPomas,neuroendocrine tumors, proliferative diabetic retinopathy, rosacea,pancreatitis, gastrointestinal bleeding, pancreatic and intestinalfistulas, Graves-Basedow opthalmopathy, glaucoma, and symptomsassociated with chemotherapy or AIDS.
 17. The method of claim 2, whereinthe hydrophilic, ethylenically unsaturated monomers are selected from2-hydroxyethyl methacrylate and hydroxypropyl methacrylate monomers. 18.The method of claim 2, wherein the copolymer comprises about 20% of2-hydroxyethyl methacrylate and about 80% hydroxypropyl methacrylate.